1902: Orderly Inheritance of Disease Observed

Archibald Garrod observes that the disease alkaptonuria is inherited according to Mendelian rules.

Alkaptonuria has several symptoms, including dark urine, dark pigmentation of cartilage and other connective tissue, and arthritis. Vitamin C and a low protein diet can relieve symptoms. In 1902, British physician Archibald Garrod, on the advice of his colleague, Bateson, demonstrated that alkaptonuria is inherited according to Mendelian rules and involves a rare recessive mutation. It was among the first conditions ascribed to a genetic cause. But the gene involved remained unknown until the 1990s.

In 1990, a French group led by J.L. Guenet identified mice with the equivalent of alkaptonuria; blackened wood shavings in the mouse boxes, caused by the mice's darkened urine, brought the mice to the scientists' attention. A few years later, they established that the mice carried a mutation on mouse chromosome 16, in a region that matches the long arm of human chromosome 3. Human geneticists soon mapped the alkaptonuria mutation to a small portion of chromosome 3.

In 1996, scientists isolated a gene from the region, which they called HGO. A variety of mutations in the HGO gene can cause alkaptonuria; most of the mutations leading to disease change parts of the gene that normally are conserved between the human gene and the equivalent gene in other species.

The number of disease genes scientists understand grew rapidly toward the end of the 20th century. By the year 2000, the catalog of human genes and genetic disorders - at least as cataloged in the resource Mendelian Inheritance in Man - had surpassed 11,000 entries.